BRCA1/2 variants and copy number alterations status in non familial triple negative breast cancer and high grade serous ovarian cancer.

BACKGROUND: While the role of BRCA1/2 genes in familial breast and ovarian cancer is well established, their implication in the sporadic form of both cancers is still controversial. With the development of poly (ADP-ribose) polymerase (PARP) inhibitors, the exact relationship between BRCA1/2 genes and sporadic triple negative breast cancer/high grade serous carcinoma (TNBC/HGSC) needs to be further investigated. Therefore, we conducted a study in which we analyze BRCA1/2 point mutations and copy number alterations in Moroccan patients suffering from TNBC/HGSC. METHODS: To achieve our goal, we analyzed BRCA1/2 genes in the FFPE tissue blocks and blood samples of 65 TNBC/HGSC selected patients, using next generation sequencing technology. RESULTS: From the 65 successfully sequenced patients in our cohort, we detected five-point variants in six different patients, four variants were classified as pathogenic and one of unknown significance. Regarding copy number alterations we detected one copy number loss in BRCA1 gene and one copy number gain in BRCA2 gene. The genetic screening of BRCA1/2 genes using these patients' genomic DNA indicated that five harbored a germline genetic alteration. While three harbored a somatic genetic alteration. To the best of our knowledge, three-point variants detected in our study have never been reported before. CONCLUSION: According to the results found in the present study, in a population without a family history of cancer, the possibility of a BRCA1/2 somatic pathogenic variant in high grade serous carcinoma is 7%. While for Triple negative breast cancer somatic point variants and copy number alterations seems to be a very rare genetic event.

Epidemiological Profile and Clinicopathological, Therapeutic, and Prognostic Characteristics of Nasopharyngeal Carcinoma in Northern Morocco.

BACKGROUND: Nasopharyngeal carcinoma is a multifactorial disease mainly affecting the Asian and North African populations including Morocco. This study aimed to determine the epidemiological profile of nasopharyngeal carcinoma in Northern Morocco as well as its clinicopathological, therapeutic, and prognostic characteristics. METHODS: 129 patients with nasopharyngeal carcinoma followed at the regional center of oncology of Tangier in the period between April 2017 and July 2019, and diagnosed elsewhere from March 2000 to February 2019, were included in this study. Statistical analysis of the data was realized using Statistical Package for the Social Sciences (SPSS) software. RESULTS: Nasopharyngeal carcinoma (NPC) represented 5% of all cases with a median age of 50. The most affected age group was 40-54 years (41.1%). Of all patients, 65.9% were men and 34.1% were women with a sex ratio of 1.93 (Male/Female). Undifferentiated nasopharyngeal carcinomas were the most common histological type affecting 96.12% of patients. At diagnosis, the majority of patients (82.2%) had an advanced stage of NPC (III, VIa, b, c) including 5.4% of metastatic cases (IVc). Most cases (86%) had lymph node involvement with cervical mass being the most common clinical presentation. 81.4% of patients received radiotherapy combined with chemotherapy. Among these patients, 54.3% had concurrent radiochemotherapy preceded by induction chemotherapy. The 5-year overall survival (OS) was 86.8% for all patients. It represented 91.3% for early stages, 87.9% for locally advanced stages, and 57.1% for the metastatic stage significantly. The disease-free survival (DFS) at 5 years was 87.6% knowing that relapse occurred in 16 cases. CONCLUSIONS: Nasopharyngeal carcinoma is a particular disease with a late declaration. It is common in Morocco as is the case in other endemic areas with a high prevalence. Patients' survival is significantly influenced by disease staging.

Salivary Cytokines as Potential Diagnostic Biomarkers for Systemic Lupus Erythematosus Disease.

Systemic lupus erythematosus (SLE) is a complex autoimmune inflammatory disease characterized by an unknown etiology and a highly variable clinical presentation. This clinical heterogeneity might be explained by dysregulation of tolerance to self and apoptotic mechanisms, overproduction of autoantibodies, and abnormal cytokine levels. Cytokine imbalance levels have been associated with disease activity and severity in SLE patients. In the last years, salivary cytokines related to SLE have gained significant attention and researchers have begun to focus on the identification of cytokines in the saliva of SLE patients using it as a diagnostic fluid for the inflammatory process underlying SLE. This review highlights and summarizes recent studies revealing the cytokines that have been identified in the saliva of individuals with SLE. Data reported and discussed in this report may provide useful additional information to better understand the mechanisms associated with the disease.

Contribution of BRCA1 and BRCA2 germline mutations to early onset breast cancer: a series from north of Morocco.

BACKGROUND: To date, the contribution of BRCA1/2 mutations in Moroccan early onset breast cancer patients remains unknown. Here we assess these genetic alterations for the first time in a cohort from North of Morocco. METHODS: Thirty-three patients diagnosed with breast cancer at the age of ≤40 years were recruited irrespective of breast and/or ovarian cancer family history. Coding regions and intron-exon boundaries of BRCA1 and BRCA2 genes were sequenced from peripheral blood DNA using Ion Proton (Thermo Fisher Scientific) next generation sequencing platform. RESULTS: Overall, five BRCA germline mutations were identified (15.1%). The frequency of mutations among patients with family history of breast cancer was 16.7%. Three mutations were found in BRCA1 (9%) and two within the BRCA2 gene (6%). These are three frameshift mutations (c.798_799del, c.2125_2126insA, c.5116_5119delAATA), one missense (c.116G > A) and one nonsense mutation (c.289G > T). The mutation c.5116_5119delAATA has a founder effect in North Africa. Moreover, one variant of unknown significance was identified in BRCA2 (c.4090A > G). Most BRCA mutations carriers (80%) had no family history of breast cancer. CONCLUSION: Our data do not support the hypothesis that BRCA mutations alone explain the higher frequency of breast cancer in Moroccan young women. The young age (≤40 years) for breast cancer diagnosis seems to be strongly predictive of BRCA mutation status in Moroccan patients. These results will help in decision making with regard to genetic counseling and testing in the national scale.

XmnI Polymorphism in Sickle Cell Disease in North Morocco.

Sickle cell disease is one of the most common severe monogenic disorders in the world. The -158 XmnI polymorphism (C>T) of the Gγ-globin gene promoter is known to be associated with increased expression of the Gγ-globin gene, thus, higher production of Hb F and lesser clinical severity. This study aims to determine the frequency of the XmnI polymorphism and its association with Hb F levels as a modulating factor of sickle cell disease severity in north Moroccan patients. Three hundred and eight subjects carrying the sickle cell mutation and 160 healthy individuals were recruited at the regional hospital of Larache, Morocco. The complete blood count and the Hb F levels were analyzed. The XmnI polymorphism was determined by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique and statistical analysis were done using the Statistical Package for Social Sciences software version 20. Our results estimated the allelic frequency of the XmnI polymorphism in our population at 15.8%. Out of 468 samples, 7.6% were homozygous [+/+] and 16.4% were heterozygous [+/-] for the XmnI polymorphism. This polymorphism was revealed at 20.6% in SS patients, 24.2% in AS carriers, 28.6% in Hb S (HBB: c.20A>T)/ß-thalassemia (ß-thal) patients and 22.5% in AA subjects. The north Moroccan sickle cell disease patients have shown a low frequency of the XmnI polymorphism. This was later found to be associated with high Hb F levels and mild clinical severity.

Clinicopathologic and prognostic features of breast cancer in young women: a series from North of Morocco.

BACKGROUND: Literature data reported a higher frequency of breast cancer in young women (BCYW) in developing countries. BCYW is associated with delayed diagnosis, aggressive biology and poor prognosis. However, our knowledge of biological profile, treatment received and outcome of young patients is still limited in Morocco. We propose to analyze clinicopathologic, therapeutic and prognostic features of BCYW among a series of patients native and/or inhabitant of North of Morocco. METHODS: We carried out a retro-prospective study of 331 infiltrating breast cancer cases registered between January 2010 and December 2015. Details of tumor pathology, treatment and outcome were collected. Disease-Free Survival (DFS) and Overall Survival (OS) were assessed by Kaplan-Meier analysis. RESULTS: A total of 82 patients were diagnosed with breast cancer at the age of 40 or younger (24.8%). Median age was 36 years. More than one quarter (26%) of patients had family history of breast or ovarian cancer. Advanced stages accounted for 34.2% of cases. Median tumor diameter was 2.8 cm. Intermediate and high-grade tumors represented 47.6% and 40.2%, respectively. Nodal involvement was present in 58.5% and lymphovascular invasion was found in 47.7% of the patients. About two thirds (66.2%) of tumors were hormone receptor positive, 29.2% over-expressed HER2 receptor and 23% were triple negative. Patients underwent breast conserving surgery in 38.2% of cases, 61.7% were offered adjuvant chemotherapy and 84.6% received hormone therapy. Five-year DFS and OS were respectively 88.9% and 75.6%. Locoregional recurrence occurred in 2.8% of cases and 8.3% of patients developed distant metastases. CONCLUSION: Our findings are in accordance with previous studies that have shown a higher frequency of breast cancer among Moroccan young women. In line with literature data, clinicopathologic profile seems to be aggressive and prognosis is pejorative in our series.

Colorectal Cancer: From Genetic Landscape to Targeted Therapy.

Colorectal cancer (CRC) is the third most common cancer type and the second cause of death worldwide. The advancement in understanding molecular pathways involved in CRC has led to new classifications based on the molecular characteristics of each tumor and also improved CRC management through the integration of targeted therapy into clinical practice. In this review, we will present the main molecular pathways involved in CRC carcinogenesis, the molecular classifications. The anti-VEGF and anti-EGFR therapies currently used in CRC treatment and those under clinical investigation will also be outlined, as well as the mechanisms of primary and acquired resistance to anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Targeted therapy has led to great improvement in the treatment of metastatic CRC. However, there has been variability in CRC treatment outcomes due to molecular heterogeneity in colorectal tumors, which underscores the need for identifying prognostic and predictive biomarkers for CRC-targeted drugs.

Current overview and special considerations for second breast cancer in Hodgkin lymphoma survivors.

Second breast cancer (SBC) is the most common solid cancer among Hodgkin Lymphoma (HL) female survivors. We reviewed the related modifying risk factors, radiation-induced carcinogenesis, tumors characteristics, management specificities, prevention and surveillance modalities based on current evidence. The risk of developing SBC may be influenced essentially by the age at HL treatment, follow-up latency, dose of irradiation received and the extent of irradiated field. SBCs generally develop at younger age, they are often bilateral, and exhibit more aggressive biological features and worse prognosis. No firm answer about the benefits of breast surveillance is provided by literature, but compelling evidence tends toward a clinical benefit in early detection. Increasing awareness among health providers' care and current survivors as well as the implementation of screening measures is crucial. Great efforts are ongoing in individualizing treatment strategies for future HL patients and response-adapted approaches are holding promise in prevention of these second malignancies.

Screening of the duplication 24 pb of ARX gene in Moroccan patients with X-linked Intellectual Disability.

OBJECTIVE: Intellectual Disability (ID) represents a neuropsychiatric disorder, which its etiopathogenesis remains insufficiently understood. Mutations in the Aristaless Related Homeobox gene (ARX) have been identified to cause syndromic and nonsyndromic (NS-ID). The most recurrent mutation of this gene is a duplication of 24pb, c.428-451dup. Epidemiological and genetic studies about ID in the Moroccan population remain very scarce, and none study is carried out on the ARX gene. This work aimed to study c.428-451dup (24 bp) mutation in the exon 2 of the ARX gene in 118 males' Moroccan patients with milder NS-ID to evaluate if the gene screening is a good tool for identifying NS-ID. RESULTS: Our mutational analysis did not show any dup(24pb) in our patients. This is because based on findings from previous studies that found ARX mutations in 70% of families with NS-ID, and in most cases, 1.5-6.1% of individuals with NS-ID have this duplication. Since 1/118 = 0.0084 (0.84%) is not much different from 1.5%, then it is reasonable that this could a sample size artifact. A complete screening of the entire ARX gene, including the five exons, should be fulfilled. Further investigations are required to confirm these results.

Intellectual Disability in Morocco: A Pilot Study.

Objective: Intellectual disability (ID) is a heterogeneous group of disorders characterized by a congenital limitation in intellectual functioning and adaptive behaviour. Our present work aimed to describe the demographic and clinical characteristics in a series of Moroccan individuals with ID living in Fez city and its regions. Design: It was a prospective and descriptive exploratory monocentric study carried out between October 2014 and July 2019. We selected 186 patients diagnosed with ID at three different centers in Fez city. The data were processed and analyzed using the IBM SPSS version 24. Results: Our data revealed a high frequency of male patients with ID (67.2% in male patients vs. 32.8% in female patients). The male-to-female ratio was 2.04. The mean age of our patients was 15.52 ±6.59 years (mean±SD), ranging between 2 and 36 years. The mean age of fathers and mothers at the birth of their child with ID was 36 and 28 years, respectively. Several abnormal behaviors were observed: 23.1 percent delayed language learning, 17.7 percent anxiety, 12.9 percent aggressiveness, 19.18 percent concentration problems, and 5.4 percent hyperactivity. Epileptic seizures were the most common mental health disorder (21.72%) observed in our patients. Approximately 25 percent of patients with epilepsy took antiepileptic and/or neuroleptics to prevent the occurrence of seizures. Conclusion: A significant correlation was observed between ID associated to genetic causes and the increase of consanguinity rate.

Proteomics characterization of CENP-B epitope in Moroccan scleroderma patients with anti-centromere autoantibodies.

BACKGROUND: Anti-centromere auto-antibodies (ACA) have been described as a marker in Systemic sclerosis (SSc) disease. CENP-B is the major centromere auto-antigen recognized by SSc patients with positive ACA. Our aim was to characterize the major epitope involved in the anti-CENP-B immune response of Moroccan SSc patients. PATIENTS AND METHOD: For identification of SSc biomarkers, 80 sera from patients with SSc and systemic lupus erythematosus (SLE) were screened by indirect immunofluorescence test (IIF) to assess the presence of ANA reactivity. Immunoblotting analysis was performed for 11 sera with positive ACA using the N-terminal and C-terminal region of CENP-B protein as antigens. RESULTS: 29 out of 30 (96, 66 %) patients with SSc had positive ANA. 11 out of 30 (36, 67 %) patients were ACA positive and 6 of them produced auto-antibodies against Nt-CENPB antigen. Two of these 6 Nt-CENPB positive sera produced also other auto-antibodies associated to primary biliary cirrhosis. None of all sera tested showed reactivity against Ct-CENPB. CONCLUSION: Our data showed, for the first time in Morocco, that the Nt-CENPB contains a major epitope for Moroccan SSc patients. These findings could provide additional information that would contribute to improving the diagnosis and management of these patients.

Hemoglobinopathies in the North of Morocco: Consanguinity Pilot Study.

Consanguinity is a social behavior characterized by the arrangement of marriages between relatives. It coincides generally with the geographic distribution of recessive genetic diseases as it increases the likelihood of homozygosis and, consequently, the incidence of their pathologies in the population. In this pilot study, we assess the effect of inbreeding on the burden of hemoglobinopathies in Northern Morocco. From January 2016 to December 2018, 197 children born in the studied region to three ancestral generations and diagnosed with hemoglobinopathies were subject to investigation. The rate of consanguinity in the parents' generation of children with hemoglobinopathies was 50.25%, with first cousin marriages accounting for 68.69% of consanguineous unions (FI = 0.02). The corresponding rates in the general population, based on a sample of N = 900, were 29.67% and 82.02%, respectively. The marriages between first cousins are the most common among the other types of consanguineous unions. Our study propounds that consanguinity substantially contributes to the hemoglobinopathy burden in the studied region and has changed little over time. Refraining from consanguineous marriages and detecting couples at risk could contribute to the reduction of the incidence of genetic diseases in our country.

Alpha-Thalassemia in North Morocco: Prevalence and Molecular Spectrum.

Unlike the other hemoglobinopathies, few researches have been published concerning α-thalassemia in Morocco. The epidemiological features and the mutation spectrum of this disease are still unknown. This regional newborn screening is the first to study α-thalassemia in the north of Morocco. During the period from January 2015 to December 2016, 1658 newborns umbilical blood samples were investigated. Suspected newborns were screened for α-globin defects using Gap-PCR and Multiplex Ligation-dependent Probe Amplification technique. The prevalence of α-thalassemia, its mutation spectrum, and its allelic frequencies were described for the first time in Morocco. Six different α-globin genetic disorders were detected in 16 neonates. This screening valued the prevalence of α-thalassemia in the studied population at 0.96% and showed the wide mutation spectrum and the heterogeneous geographical distribution of the disease. A high rate of carriers was observed in Laouamra, a rural commune in Larache province. Heterogeneity of α-globin alleles in Morocco explains the high variability of α-thalassemia severity. This diversity reflects the anthropological history of the country. These results would contribute to the prevention of thalassemia in Morocco directing the design of a nationwide screening strategy and awareness campaign.

Salivary Biomarkers in Systemic Sclerosis Disease.

Scleroderma or systemic sclerosis (SSc) is frequently detected at an advanced stage due to diagnosis difficulties. Salivary biomarkers, if existing, could be used for predictive diagnosis of this disease. Human saliva contains a large number of proteins that can be used for diagnosis and are of great potential in clinical research. The use of proteomic analysis to characterize whole saliva (WS) in SSc has gained an increasing attention in the last years and the identification of salivary proteins specific for SSc could lead to early diagnosis or new therapeutic targets. This review will present an overview about the use of WS in SSc studies. The proteomic technologies currently used for global identification of salivary proteins in SSc, as well as the advantages and limitations for the use of WS as a diagnostic tool, will be presented.

Immunological and Clinical Characteristics of Systemic Lupus Erythematosus: A Series from Morocco.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease with a high female predominance. To date, studies about SLE in Morocco are few. This retrospective study describes the clinical and immunological features in a series of 50 SLE Moroccan patients in University Hospital Center of Rabat, Morocco, between December 2011 and December 2013. All patients were screened for antinuclear antibodies (ANA) and anti-DNA antibodies by indirect immunofluorescence, followed by identification of anti-extractable nuclear antigen antibodies by ELISA. The female to male ratio was 6.1:1. Mean age was 31.72 years. The main clinical manifestations were arthritis (82%), mucocutaneous manifestations (80%), renal manifestations (50%), and hematological features (46%). Of the mucocutaneous features, the highest frequencies were observed in the malar rash (68%) and photosensitivity (60%). Of the hematological features, lymphopenia was most frequently observed in 30% of patients, followed by hemolytic anemia in 16% and leucopenia and thrombocytopenia in 8%. Central nervous system was involved in 10%. ANA were found in 88%, anti-DNA antibodies in 56%, and anti-Sm antibodies in 50%. Anti-SSA, anti-SSB, anti-Sm/RNP, and anti-Scl70 antibodies were detected in 38%, 10%, 48%, and 8%, respectively. Our data show that, in our patients, the main clinical and immunological features of SLE remain comparable to patients from other Arab countries.